Pyrimidine compounds containing seven-membered fused ring systems

ABSTRACT

The present invention encompasses compounds of general formula (1) 
                         
wherein
     A, B, X, R 1  to R 3  are defined as in claim  1 , which are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, and their use for preparing a medicament having the above-mentioned properties.

The present invention relates to new pyrimidines of general formula (1)

wherein the groups A, B, X, R¹ to R³ have the meanings given below inthis specification, the isomers thereof, processes for preparing thesepyrimidines and their use as medicaments.

BACKGROUND OF THE INVENTION

Tumour cells that acquire the properties for invasion andmetastasisation require specific survival signals. These signals allowthem to overcome special apoptosis mechanisms (anoikis) which aretriggered, inter alia, by the loss of cell adhesion. In this process,focal adhesion kinase (FAK/PTK2) is one of the essential signalmolecules which on the one hand controls cell-matrix interactionsthrough so-called ‘focal adhesions’ and on the other hand impartsanoikis resistance. Interference with these mechanisms by inhibitingPTK2 may lead to the apoptotic cell death of tumour cells and limit theinvasive and metastasising growth of tumours. In addition, focaladhesion kinase has major significance for the growth, migration andsurvival of tumour-associated endothelial cells. An anti-angiogenicactivity may therefore also be achieved by inhibiting PTK2.

Pyrimidines are generally known as inhibitors of kinases. Thus, forexample, International Patent Application WO 2008038011 describespyrimidines as aurora kinase inhibitors, these pyrimidines having, assubstituents, an oxy-methyl-piperidine group in the 4 position andfluorine in the 5 position.

The aim of the present invention is to indicate new active substanceswhich can be used for the prevention and/or treatment of diseasescharacterised by excessive or abnormal cell proliferation.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that, surprisingly, compounds of general formula (1),wherein the groups A, B, X and R¹-R³ have the meanings given below, actas inhibitors of specific tyrosine-kinases. Thus, the compoundsaccording to the invention may be used for example for treating diseasesconnected with the activity of specific tyrosine-kinases andcharacterised by excessive or abnormal cell proliferation.

The present invention relates to compounds of general formula (1)

wherein

A denotes a group, optionally substituted by one or more identical ordifferent R¹, selected from among C₃₋₁₀cycloalkyl, 3-8 memberedheterocycloalkyl, C₆₋₁₅aryl and 5-12 membered heteroaryl;

B denotes a 9-11 membered carbo- or heterobicyclic ring system,optionally substituted by one or more identical or different R²;

X denotes O, S or CH₂;

R¹ and R² each independently of one another denote hydrogen or a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(c) and/or R^(b);

R³ denotes a group selected from among hydrogen, halogen, —OR^(c),—OCF₃, —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;

each R^(a) is selected independently of one another from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl;

each R^(b) is a suitable group and is independently selected from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c),═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c),—N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c),—S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c),—OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),—C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c),—C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g)[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c);

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(d) is a suitable group and is independently selected from among═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e), ═NOR^(e),═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N {[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e);

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(f) is a suitable group and is independently selected from amonghalogen and —CF₃; and

each R^(g) independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl;

optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

In one aspect the invention relates to compounds of general formula (1),wherein X denotes oxygen.

In another aspect the invention relates to compounds of general formula(1a),

wherein

A denotes a group, optionally substituted by one or more identical ordifferent R¹, selected from among C₃₋₁₀cycloalkyl, 3-8 memberedheterocycloalkyl, C₆₋₁₅aryl and 5-12 membered heteroaryl;

R¹ and R² each independently of one another denote hydrogen or a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(c) and/or R^(b);

R³ denotes a group selected from among hydrogen, halogen, —OR^(c),—OCF₃, —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;

each R^(a) is selected independently of one another from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl;

each R^(b) is a suitable group and is independently selected from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c),═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c),—N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c),—S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c),—OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),—C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c),—C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c);

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(d) is a suitable group and is independently selected from among═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e), ═NOR^(e),═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O) SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e);

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(f) is a suitable group and is independently selected from amonghalogen and —CF₃; and

each R^(g) independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl; and W and Y independently of one another represent CH₂,O, N—R^(e) or N—OR^(e).

In another aspect the invention relates to compounds of general formula(1b),

wherein

A denotes a group, optionally substituted by one or more identical ordifferent R¹, selected from among C₃₋₁₀cycloalkyl, 3-8 memberedheterocycloalkyl, C₆₋₁₅aryl and 5-12 membered heteroaryl;

R¹ and R² each independently of one another denote hydrogen or a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(c) and/or R^(b);

R³ denotes a group selected from among hydrogen, halogen, —OR^(c),—OCF₃, —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;

each R^(a) is selected independently of one another from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl;

each R^(b) is a suitable group and is independently selected from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c),═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c),—N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c),—S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c),—OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),—C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c),—C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c);

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(d) is a suitable group and is independently selected from among═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e), ═NOR^(e),═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), [N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e);

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(f) is a suitable group and is independently selected from amonghalogen and —CF₃; and

each R^(g) independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl; and W and Y independently of one another represent CH₂,O, N—R^(e) or N—OR^(e). In another aspect the invention relates tocompounds of general formula (1c),

wherein

A denotes a group, optionally substituted by one or more identical ordifferent R¹, selected from among C₃₋₁₀cycloalkyl, 3-8 memberedheterocycloalkyl, C₆₋₁₅aryl and 5-12 membered heteroaryl;

R¹ and R² each independently of one another denote hydrogen or a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(c) and/or R^(b);

R³ denotes a group selected from among hydrogen, halogen, —OR^(c),—OCF₃, —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;

each R^(a) is selected independently of one another from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl;

each R^(b) is a suitable group and is independently selected from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c),═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c),—N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c),—S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c),—OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),—C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c),—C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c);

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(d) is a suitable group and is independently selected from among═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e), ═NOR^(e),═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e);

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(f) is a suitable group and is independently selected from amonghalogen and —CF₃; and

each R^(g) independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl; and

W and Y independently of one another represent CH₂, O, N—R^(e) orN—OR^(e). In another aspect the invention relates to compounds ofgeneral formula (1), (1a), (1b) or (1c), wherein A is phenyl.

In another aspect the invention relates to compounds of general formula(1d),

wherein

W and Y each independently of one another represent CH₂, O, N—R^(e) orN—OR^(e), and

R¹ denotes hydrogen or a group selected from among R^(a), R^(b) andR^(a) substituted by one or more identical or different R^(c) and/orR^(b);

R² denotes hydrogen or a group selected from among R^(a), R^(b) andR^(a) substituted by one or more identical or different R^(c) and/orR^(b);

R³ denotes a group selected from among hydrogen, halogen, —OR^(c),—OCF₃, —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;

each R^(a) is selected independently of one another from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl;

each R^(b) is a suitable group and is independently selected from among═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c),═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c),—N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c),—S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c),—OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),—C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c),—C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c);

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(d) is a suitable group and is independently selected from among═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e), ═NOR^(e),═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e);

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl;

each R^(f) is a suitable group and is independently selected from amonghalogen and —CF₃; and

each R^(g) independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, and R^(1′) and R^(1″) each independently of one anotherdenote a group selected from among hydrogen, halogen and —OR^(c);

In another aspect the invention relates to compounds of general formula(1), (1a), (1b), (1c) or (1d), wherein R³ is Cl or CF₃.

In another aspect the invention relates to a compound selected from thegroup consisting of

In another aspect the invention relates to compounds, or thepharmaceutically effective salts thereof, of general formula (1), (1a),(1b), (1c) or (1d) for use as medicaments.

In another aspect the invention relates to compounds, or thepharmaceutically effective salts thereof, of general formula (1), (1a),(1b), (1c) or (1d) for preparing a medicament with an antiproliferativeand/or pro-apoptotic activity.

In another aspect the invention relates to pharmaceutical preparationscontaining as active substance one or more compounds of general formula(1), (1a), (1b), (1c) or (1d) or the physiologically acceptable saltsthereof optionally in combination with conventional excipients and/orcarriers.

In another aspect the invention relates to the use of compounds ofgeneral formula (1), (1a), (1b), (1c) or (1d) for preparing a medicamentfor the treatment and/or prevention of cancer, infections, inflammationsor autoimmune diseases.

In another aspect the invention relates to pharmaceutical preparationscomprising a compound of general formula (1), (1a), (1b), (1c) or (1d)and at least one further cytostatic or cytotoxic active substance,different from formula (1), (1a), (1b), (1c) or (1d), optionally in theform of the tautomers, the racemates, the enantiomers, the diastereomersand the mixtures thereof, and optionally the pharmacologicallyacceptable acid addition salts thereof.

DEFINITIONS

As used herein, the following definitions apply, unless statedotherwise:

Alkyl is made up of the sub-groups saturated hydrocarbon chains andunsaturated hydrocarbon chains, while the latter may be furthersubdivided into hydrocarbon chains with a double bond (alkenyl) andhydrocarbon chains with a triple bond (alkynyl). Alkenyl contains atleast one double bond, alkynyl contains at least one triple bond. If ahydrocarbon chain were to carry both at least one double bond and alsoat least one triple bond, by definition it would belong to the alkynylsub-group. All the sub-groups mentioned above may further be dividedinto straight-chain (unbranched) and branched. If an alkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon atoms, independently of oneanother.

Examples of representatives of individual sub-groups are listed below.

Straight-Chain (Unbranched) or Branched Saturated Hydrocarbon Chains:

methyl; ethyl; n-propyl; isopropyl (1-methylethyl); n-butyl;1-methylpropyl; isobutyl (2-methylpropyl); sec.-butyl (1-methylpropyl);tert.-butyl (1,1-dimethylethyl); n-pentyl; 1-methylbutyl; 1-ethylpropyl;isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl;2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl;2-methyl-pentyl; 3-methylpentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl;2,2-dimethylpentyl; 2,3-dimethylpentyl; 2,4-dimethylpentyl;3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl;n-nonyl; n-decyl etc.

Straight-Chain (Unbranched) or Branched Alkenyl:

vinyl (ethenyl); prop-1-enyl; allyl (prop-2-enyl); isopropenyl;but-1-enyl; but-2-enyl; but-3-enyl; 2-methyl-prop-2-enyl;2-methyl-prop-1-enyl; 1-methyl-prop-2-enyl; 1-methyl-prop-1-enyl;1-methylidenepropyl; pent-1-enyl; pent-2-enyl; pent-3-enyl; pent-4-enyl;3-methyl-but-3-enyl; 3-methyl-but-2-enyl; 3-methyl-but-1-enyl;hex-1-enyl; hex-2-enyl; hex-3-enyl; hex-4-enyl; hex-5-enyl;2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl;2-methylidene-3-methylbutyl; 2,3-dimethyl-but-1-enyl; hexa-1,3-dienyl;hexa-1,4-dienyl; penta-1,4-dienyl; penta-1,3-dienyl; buta-1,3-dienyl;2,3-dimethylbuta-1,3-diene etc.

Straight-Chain (Unbranched) or Branched Alkynyl:

ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl; but-3-ynyl;1-methyl-prop-2-ynyl etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, all the isomericforms being included.

By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl etc. without any further definition are meantunsaturated hydrocarbon groups with the corresponding number of carbonatoms and a double bond, all the isomeric forms, i.e. (Z)/(E) isomers,being included where applicable.

By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl,octadienyl, nonadienyl, decadienyl etc. without any further definitionare meant unsaturated hydrocarbon groups with the corresponding numberof carbon atoms and two double bonds, all the isomeric forms, i.e.(Z)/(E) isomers, being included where applicable.

By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl etc. without any further definition are meantunsaturated hydrocarbon groups with the corresponding number of carbonatoms and a triple bond, all the isomeric forms being included.

By the term heteroalkyl are meant groups which can be derived from thealkyl as defined above in its broadest sense if, in the hydrocarbonchains, one or more of the groups —CH₃ are replaced independently of oneanother by the groups —OH, —SH or —NH₂, one or more of the groups —CH₂—are replaced independently of one another by the groups —O—, —S— or—NH—, one or more of the groups

are replaced by the group

one or more of the groups ═CH— are replaced by the group ═N—, one ormore of the groups ═CH₂ are replaced by the group ═NH or one or more ofthe groups ≡CH are replaced by the group ≡N, while overall there mayonly be a maximum of three heteroatoms in a heteroalkyl, there must beat least one carbon atom between two oxygen atoms and between twosulphur atoms or between one oxygen and one sulphur atom and the groupas a whole must be chemically stable.

It is immediately apparent from the indirect definition/derivation fromalkyl that heteroalkyl is made up of the sub-groups saturatedhydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl,and one further subdivision may be carried out into straight-chain(unbranched) and branched. If a heteroalkyl is substituted, thesubstitution may be mono- or polysubstitution in each case, at all thehydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms,independently of one another. Heteroalkyl itself may be linked to themolecule as a substituent both via a carbon atom and via a heteroatom.

Typical examples are listed below:

dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl;2-dimethyl-aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl,2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl;diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl);diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl,3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl,2-di-isopropylaminoethyl); bis-2-methoxyethylamino;[2-(dimethylamino-ethyl)-ethyl-amino]-methyl;3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl;2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy;methoxymethyl; 2-methoxyethyl etc.

Halogen denotes fluorine, chlorine, bromine and/or iodine atoms.

Haloalkyl is derived from alkyl as hereinbefore defined in its broadestsense, when one or more hydrogen atoms of the hydrocarbon chain arereplaced independently of one another by halogen atoms, which may beidentical or different. It is immediately apparent from the indirectdefinition/derivation from alkyl that haloalkyl is made up of thesub-groups saturated halohydrocarbon chains, haloalkenyl andhaloalkynyl, and further subdivision may be made into straight-chain(unbranched) and branched. If a haloalkyl is substituted, thesubstitution may be mono- or polysubstitution in each case, at all thehydrogen-carrying carbon atoms, independently of one another.

Typical examples include —CF₃; —CHF₂; —CH₂F; —CF₂CF₃; —CHFCF₃; —CH₂CF₃;—CF₂CH₃; —CHFCH₃; —CF₂CF₂CF₃; —CF₂CH₂CH₃; —CF═CF₂; —CCl═CH₂; —CBr═CH₂;—CI═CH₂; —C≡C—CF₃; CHFCH₂CH₃; and CHFCH₂CF₃.

Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spirohydrocarbon rings, while eachsub-group may be further subdivided into saturated and unsaturated(cycloalkenyl). The term unsaturated means that in the ring system inquestion there is at least one double bond, but no aromatic system isformed. In bicyclic hydrocarbon rings two rings are linked such thatthey have at least two carbon atoms in common. In spirohydrocarbon ringsone carbon atom (spiroatom) is shared by two rings. If a cycloalkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon atoms, independently of oneanother. Cycloalkyl itself may be linked to the molecule as substituentvia any suitable position of the ring system.

Typical examples of individual sub-groups are listed below.

Monocyclic Saturated Hydrocarbon Rings:

cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc.

Monocyclic Unsaturated Hydrocarbon Rings:

cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl;cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl;cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl;cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3-dienyl;cyclopenta-1,4-dienyl; cyclopenta-1,3-dienyl; cyclopenta-2,4-dienyl;cyclohexa-1,3-dienyl; cyclohexa-1,5-dienyl; cyclohexa-2,4-dienyl;cyclohexa-1,4-dienyl; cyclohexa-2,5-dienyl etc.

Saturated and Unsaturated Bicyclic Hydrocarbon Rings:

bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl;bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl (octahydroindenyl);bicyclo[4.4.0]decyl (decahydronaphthalene); bicyclo[2,2,1]heptyl(norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl);bicyclo[2,2,1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl(norcaranyl); bicyclo-[3.1.1]heptyl (pinanyl) etc.

Saturated and Unsaturated Spirohydrocarbon Rings:

spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene etc.

Cycloalkylalkyl denotes the combination of the above-defined groupsalkyl and cycloalkyl, in each case in their broadest sense. The alkylgroup as substituent is directly linked to the molecule and is in turnsubstituted by a cycloalkyl group. The alkyl and cycloalkyl may belinked in both groups via any carbon atoms suitable for this purpose.The respective sub-groups of alkyl and cycloalkyl are also included inthe combination of the two groups.

Aryl denotes mono-, bi- or tricyclic carbon rings with at least onearomatic ring. If an aryl is substituted, the substitution may be mono-or polysubstitution in each case, at all the hydrogen-carrying carbonatoms, independently of one another. Aryl itself may be linked to themolecule as substituent via any suitable position of the ring system.

Typical examples include phenyl, naphthyl, indanyl (2,3-dihydroindenyl),1,2,3,4-tetrahydronaphthyl and fluorenyl.

Carbo-bicyclic ring systems include for example indanyl,1,2,3,4-tetrahydronaphthyl and 6,7,8,9-tetrahydrobenzocycloheptyl.

Arylalkyl denotes the combination of the groups alkyl and aryl ashereinbefore defined, in each case in their broadest sense. The alkylgroup as substituent is directly linked to the molecule and is in turnsubstituted by an aryl group. The alkyl and aryl may be linked in bothgroups via any carbon atoms suitable for this purpose. The respectivesub-groups of alkyl and aryl are also included in the combination of thetwo groups.

Typical examples include benzyl; 1-phenylethyl; 2-phenylethyl;phenylvinyl; phenylallyl etc.

Heteroaryl denotes monocyclic aromatic rings or polycyclic rings with atleast one aromatic ring, which, compared with corresponding aryl orcycloalkyl, contain instead of one or more carbon atoms one or moreidentical or different heteroatoms, selected independently of oneanother from among nitrogen, sulphur and oxygen, while the resultinggroup must be chemically stable. If a heteroaryl is substituted, thesubstitution may be mono- or polysubstitution in each case, at all thehydrogen-carrying carbon and/or nitrogen atoms, independently of oneanother. Heteroaryl itself as substituent may be linked to the moleculevia any suitable position of the ring system, both carbon and nitrogen.

Typical examples are listed below.

Monocyclic Heteroaryls:

furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl;pyrazolyl; imidazolyl; triazolyl; tetrazolyl; oxadiazolyl; thiadiazolyl;pyridyl; pyrimidyl; pyridazinyl; pyrazinyl; triazinyl; pyridyl-N-oxide;pyrrolyl-N-oxide; pyrimidinyl-N-oxide; pyridazinyl-N-oxide;pyrazinyl-N-oxide; imidazolyl-N-oxide; isoxazolyl-N-oxide;oxazolyl-N-oxide; thiazolyl-N-oxide; oxadiazolyl-N-oxide;thiadiazolyl-N-oxide; triazolyl-N-oxide; tetrazolyl-N-oxide etc.

Polycyclic Heteroaryls:

indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl;benzothiazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolyl;indazolyl; isoquinolinyl; quinolinyl; quinoxalinyl; cinnolinyl;phthalazinyl; quinazolinyl; benzotriazinyl; indolizinyl; oxazolopyridyl;imidazopyridyl; naphthyridinyl; indolinyl; isochromanyl; chromanyl;tetrahydroisoquinolinyl; isoindolinyl; isobenzotetrahydrofuryl;isobenzotetrahydrothienyl; isobenzothienyl; benzoxazolyl; pyridopyridyl;benzotetrahydrofuryl; benzotetrahydro-thienyl; purinyl; benzodioxolyl;phenoxazinyl; phenothiazinyl; pteridinyl; benzothiazolyl;imidazopyridyl; imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinyl;benzoxazinyl; dihydrobenzisothiazinyl; benzopyranyl; benzothiopyranyl;cumarinyl; isocumarinyl; chromonyl; chromanonyl; tetrahydroquinolinyl;dihydroquinolinyl; dihydroquinolinonyl; dihydroisoquinolinonyl;dihydrocumarinyl; dihydroisocumarinyl; isoindolinonyl; benzodioxanyl;benzoxazolinonyl; quinolinyl-N-oxide; indolyl-N-oxide;indolinyl-N-oxide; isoquinolyl-N-oxide; quinazolinyl-N-oxide;quinoxalinyl-N-oxide; phthalazinyl-N-oxide; indolizinyl-N-oxide;indazolyl-N-oxide; benzothiazolyl-N-oxide; benzimidazolyl-N-oxide;benzo-thiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide etc.

Hetero-bicyclic ring systems include for example dihydrobenzofuryl,dihydroisobenzofuryl, dihydroindolyl dihydroisoindolyl,dihydrobenzthiophenyl, dihydroisobenzthiophenyl, dihydroindazolyl,1,2-benzisoxazolyl, 1H-1,2-benzisoxazolyl, 1,2 benzthiazolyl,2,3-tetrahydro-1H-isoquinolinyl, 3,4-tetrahydro-2H-isoquinolinyl,tetrahydroquinolinyl, chromanyl, isochromanyl, isochromenyl,thiochromanyl, thiochromenyl, dihydro-2H-phthalazinyl,tetrahydrocinnolinyl, tetrahydroquinazolinyl, tetrahydrobenzodiazepinyland tetrahydrobenzoxazepinyl.

Heteroarylalkyl denotes the combination of the alkyl and heteroarylgroups defined hereinbefore, in each case in their broadest sense. Thealkyl group as substituent is directly linked to the molecule and is inturn substituted by a heteroaryl group. The linking of the alkyl andheteroaryl may be achieved on the alkyl side via any carbon atomssuitable for this purpose and on the heteroaryl side by any carbon ornitrogen atoms suitable for this purpose. The respective sub-groups ofalkyl and heteroaryl are also included in the combination of the twogroups.

By the term heterocycloalkyl are meant groups which are derived from thecycloalkyl as hereinbefore defined if in the hydrocarbon rings one ormore of the groups —CH₂— are replaced independently of one another bythe groups —O—, —S— or —NH— or one or more of the groups ═CH— arereplaced by the group ═N—, while not more than five heteroatoms may bepresent in total, there must be at least one carbon atom between twooxygen atoms and between two sulphur atoms or between one oxygen and onesulphur atom and the group as a whole must be chemically stable.Heteroatoms may simultaneously be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). Itis immediately apparent from the indirect definition/derivation fromcycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclichetero-rings, bicyclic hetero-rings and spirohetero-rings, while eachsub-group can also be further subdivided into saturated and unsaturated(heterocycloalkenyl). The term unsaturated means that in the ring systemin question there is at least one double bond, but no aromatic system isformed. In bicyclic hetero-rings two rings are linked such that theyhave at least two atoms in common. In spirohetero-rings one carbon atom(spiroatom) is shared by two rings. If a heterocycloalkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon and/or nitrogen atoms,independently of one another. Heterocycloalkyl itself as substituent maybe linked to the molecule via any suitable position of the ring system.

Typical examples of individual sub-groups are listed below.

Monocyclic Heterorings (Saturated and Unsaturated):

tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl;thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl; piperidinyl;piperazinyl; oxiranyl; aziridinyl; azetidinyl; 1,4-dioxanyl; azepanyl;diazepanyl; morpholinyl; thiomorpholinyl; homomorpholinyl;homopiperidinyl; homopiperazinyl; homothiomorpholinyl;thiomorpholinyl-S-oxide; thiomorpholinyl-S,S-dioxide; 1,3-dioxolanyl;tetrahydropyranyl; tetrahydrothiopyranyl; [1,4]-oxazepanyl;tetrahydrothienyl; homothiomorpholinyl-S,S-dioxide; oxazolidinonyl;dihydropyrazolyl; dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl;dihydro-pyrimidinyl; dihydrofuryl; dihydropyranyl;tetrahydrothienyl-S-oxide; tetrahydrothienyl-S,S-dioxide;homothiomorpholinyl-S-oxide; 2,3-dihydroazet; 2H-pyrrolyl; 4H-pyranyl;1,4-dihydropyridinyl etc.

Bicyclic Heterorings (Saturated and Unsaturated):

8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl;2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa-3-aza-bicyclo[3.2.1]octyl;3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo-[2.2.1]heptyl;1-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl;3,9-diaza-bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl;hexahydro-furo[3,2-b]furyl; etc.

Spiro-Heterorings (Saturated and Unsaturated):

1,4-dioxa-spiro[4.5]decyl; 1-oxa-3,8-diaza-spiro[4.5]decyl; and2,6-diaza-spiro[3.3]heptyl; 2,7-diaza-spiro[4.4]nonyl;2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl;2,8-diaza-spiro[4.5]decyl etc.

Heterocycloalkylalkyl denotes the combination of the alkyl andheterocycloalkyl groups defined hereinbefore, in each case in theirbroadest sense. The alkyl group as substituent is directly linked to themolecule and is in turn substituted by a heterocycloalkyl group. Thelinking of the alkyl and heterocycloalkyl may be achieved on the alkylside via any carbon atoms suitable for this purpose and on theheterocycloalkyl side by any carbon or nitrogen atoms suitable for thispurpose. The respective sub-groups of alkyl and heterocycloalkyl arealso included in the combination of the two groups.

By the term “suitable substituent” is meant a substituent that on theone hand is fitting on account of its valency and on the other handleads to a system with chemical stability.

By “prodrug” is meant an active substance in the form of its precursormetabolite. A distinction may be made between partly multi-partcarrier-prodrug systems and biotransformation systems. The lattercontain the active substance in a form that requires chemical orbiological metabolisation. The skilled man will be familiar with prodrugsystems of this kind (Sloan, Kenneth B.; Wasdo, Scott C. The role ofprodrugs in penetration enhancement. Percutaneous Penetration Enhancers(2nd Edition) (2006). 51-64; Lloyd, Andrew W. Prodrugs. Smith andWilliams' Introduction to the Principles of Drug Design and Action (4thEdition) (2006), 211-232; Neervannan, Seshadri. Strategies to impactsolubility and dissolution rate during drug lead optimization: saltselection and prodrug design approaches. American Pharmaceutical Review(2004), 7(5), 108.110-113). A suitable prodrug contains for example asubstance of the general formulae which is linked via an enzymaticallycleavable linker (e.g. carbamate, phosphate, N-glycoside or a disulphidegroup to a dissolution-improving substance (e.g. tetraethyleneglycol,saccharides, amino acids). Carrier-prodrug systems contain the activesubstance as such, bound to a masking group which can be cleaved by thesimplest possible controllable mechanism. The function of masking groupsaccording to the invention in the compounds according to the inventionis to neutralise the charge for improving cell uptake. If the compoundsaccording to the invention are used with a masking group, these may alsoadditionally influence other pharmacological parameters, such as forexample oral bioavailability, tissue distribution, pharmacokinetics andstability against non-specific phosphatases. The delayed release of theactive substance may also involve a sustained-release release effect. Inaddition, modified metabolisation may occur, thus resulting in a higherefficiency of the active substance or organic specificity. In the caseof a prodrug formulation, the masking group or a linker that binds themasking group to the active substance is selected such that the prodrugis sufficiently hydrophilic to be dissolved in the blood serum, hassufficient chemical and enzymatic stability to reach the activity siteand is also sufficiently hydrophilic to ensure that it is suitable fordiffusion-controlled membrane transport. Furthermore, it should allowchemically or enzymatically induced release of the active substancewithin a reasonable period and, it goes without saying, the auxiliarycomponents released should be non-toxic. Within the scope of theinvention, however, the compound without a mask or linker, and a mask,may be regarded as a prodrug which first of all has to be prepared inthe cell from the ingested compound by enzymatic and biochemicalprocesses.

LIST OF ABBREVIATIONS

abs. absolute, anhydrous

Ac acetyl

Bn benzyl

Boc tert-butyloxycarbonyl

Bu butyl

c concentration

cHex cyclohexane

d day(s)

TLC thin layer chromatography

DCM dichloromethane

DEA diethylamine

DIPEA N-ethyl-N,N-diisopropylamine (Hünig base)

DMF N,N-dimethylformamide

DMSO dimethylsulphoxide

ESI electron spray ionization

Et ethyl

EtOH ethanol

h hour(s)

O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyl-uronium

HATU

tetrafluorophosphate

hex hexyl

HPLC high performance liquid chromatography

i iso

IR infra red spectroscopy

conc. concentrated

LC liquid chromatography

Me methyl

MeOH methanol

min minute(s)

MPLC medium pressure liquid chromatography

MS mass spectrometry

NMP N-methylpyrrolidone

NP normal phase

Pd₂dba₃ tris (dibenzylideneacetone)dipalladium(0)

Ph phenyl

Pr propyl

Py pyridine

rac racemic

R_(f) (Rf) retention factor

RP reversed phase

RT ambient temperature

TBTU O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyl-uroniumtetrafluoroborate

Temp. temperature

tert. tertiary

TFA trifluoroacetic acid

THF tetrahydrofuran

t_(Ret.) retention time (HPLC)

UV ultraviolet

X-Phos 2-dicyclohexylphosphiono-2′,4′,6′ triisopropyl-1,1′-biphenyl

Features and advantages of the present invention will become apparentfrom the following detailed Examples which illustrate the fundamentalsof the invention by way of example, without restricting its scope:

Preparation of the Compounds According to the Invention

General

All the reactions are carried out—unless stated otherwise—incommercially obtainable apparatus using methods conventionally used inchemical laboratories.

Air- and/or moisture-sensitive starting materials are stored underprotective gas and corresponding reactions and manipulations using themare carried out under protective gas (nitrogen or argon).

Microwave reactions are carried out in an Initiator made by Biotage oran Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL),preferably with stirring.

Chromatography

For the preparative medium pressure chromatography (MPLC, normal phase)silica gel is used which is made by Millipore (named Granula SilicaSi-60A 35-70 μm) or C-18 RP-silica gel (RP-phase) made by Macherey Nagel(named Polygoprep 100-50 C18).

The thin layer chromatography is carried out on ready-made silica gel 60TLC plates on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (HPLC) is carried out usingcolumns made by Waters (named: XTerra Prep. MS C18, 5 μM, 30×100 mm orXTerra Prep. MS C18, 5 μm, 50×100 mm OBD or Symmetrie C18, 5 μm, 19×100mm or Sunfire C18 OBD, 19×100 mm, 5 μm or Sunfire Prep C 10 μm OBD50×150 mm or X-Bridge Prep C18 5 μm OBD 19×50 mm), Agilent (named ZorbaxSB-C8 5 μm PrepHT 21.2×50 mm) and Phenomenex (named Gemini C18 5 μm AXIA21.2×50 mm or Gemini C18 10 μm 50×150 mm), the analytical HPLC (reactioncontrol) is carried out with columns made by Agilent (named: ZorbaxSB-C8, 5 μm, 21.2×50 mm or Zorbax SB-C8 3.5 μm 2.1×50 mm) and Phenomenex(named Gemini C18 3 μm 2×30 mm).

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESI⁺ for characterising the examples are obtainedusing an HPLC-MS apparatus (high performance liquid chromatography withmass detector) made by Agilent. Compounds that elute with the injectionpeak are given the retention time t_(Ret.)=0.00.

Method A:

-   -   Column: Waters, Xterra MS C18, 2.5 μm, 2.1×30 mm, Part. No.        186000592    -   Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile (HPLC grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 120-900 m/z    -   Fragmentor: 120    -   Gain EMV: 1; Threshold: 150; Stepsize: 0.25; UV: 254 nm;        Bandwidth: 1    -   Injection: Inj. Vol. 5 μL    -   Separation: Flow 1.10 mL/min    -   Column temp.: 40° C.

Gradient: 0.00 min: 5% solvent B 0.00-2.50 min: 5% → 95% solvent B2.50-2.80 min: 95% solvent B 2.81-3.10 min: 95% → 5% solvent B

Method B:

-   -   Column: Waters, Xterra MS C18, 2.5 μm, 2.1×50 mm, Part. No.        186000594    -   Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile with 0.1% HCOOH    -   Detection: MS: Positive and negative mode    -   Mass range: 100-1200 m/z    -   Fragmentor: 70    -   Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 254 nm as well        as 230 nm    -   Injection: Standard 1 μL    -   Flow: 0.6 mL/min    -   Column temp.: 35° C.    -   Gradient: 0.00 min. 5% solvent B        -   0.00-2.50 min: 5%→95% solvent B        -   2.50-4.00 min 95% solvent B        -   4.00-4.50 min: 95%→5% solvent B        -   4.50-6.00 min: 95% solvent A

Method C:

-   -   Column: Waters, X-Bridge C18, 3.5 μm, 2.1×50 mm,    -   Eluant: A: H₂O with 10 mM NH₃; B: acetonitrile with 10 nM NH₃    -   Detection: MS: Positive and negative mode    -   Mass range: 100-800 m/z    -   Fragmentor: 70    -   Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm    -   Injection: Standard 1 μL    -   Flow: 0.8 mL/min    -   Column temp.: 25° C.    -   Gradient: 0.00 min 2% solvent B        -   0.00-4.00 min: 2%→98% solvent B        -   4.00-6.00 min: 98% solvent B

Method D:

-   -   Column: Waters, X-Bridge C18, 3.5 μm, 2.1×50 mm,    -   Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile with 0.1% HCOOH    -   Detection: MS: Positive and negative mode    -   Mass range: 100-800 m/z    -   Fragmentor: 70    -   Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm    -   Injection: Standard 1 μL    -   Flow: 0.8 mL/min    -   Column temp.: 35° C.    -   Gradient: 0.00 min: 2% solvent B        -   0.00-4.00 min: 2%→98% solvent B        -   4.00-6.00 min: 98% solvent B

Method E:

-   -   Column: Phenomenex Gemini C18, 3.0 μm, 2.0×50 mm,    -   Eluant: A: H₂O with 10 mM NH₃; B: acetonitrile with 10 nM NH₃    -   Detection: MS: Positive and negative mode    -   Mass range: 100-800 m/z    -   Fragmentor: 70    -   Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm    -   Injection: Standard 1 μL    -   Flow: 1.0 mL/min    -   Column temp.: 35° C.    -   Gradient: 0.00 min: 2% solvent B        -   0.00-3.50 min: 2%→98% solvent B        -   3.50-6.00 min: 98% solvent B

Method F:

-   -   Column: Phenomenex Gemini C18, 3.0 μm, 2.0×50 mm,    -   Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile with 0.1% HCOOH    -   Detection: MS: Positive and negative mode    -   Mass range: 100-800 m/z    -   Fragmentor: 70    -   Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm    -   Injection: Standard 1 μL    -   Flow: 1.0 mL/min    -   Column temp.: 35° C.    -   Gradient: 0.00 min: 2% solvent B        -   0.00-3.50 min: 2%→98% solvent B        -   3.50-6.00 min: 95% solvent B

The compounds according to the invention are prepared by the methods ofsynthesis described below, in which the substituents of the generalformulae have the meanings specified hereinbefore. These methods areintended to illustrate the invention without restricting it to theircontent or limiting the scope of the compounds claimed to theseExamples. Where the preparation of the starting compounds is notdescribed, they are commercially obtainable or may be preparedanalogously to known compounds or methods described herein. Substancesdescribed in the literature are prepared according to the publishedmethods of synthesis.

Example compounds of type (1) are prepared from 2,4-dichloro-pyrimidinesA-1 by nucleophilic aromatic substitution of the chlorine in the 4position of the pyrimidine with a phenol OR², a thiophenol SR² or bycoupling benzylmetal halides HalMetR² and subsequently exchanging thesecond chlorine by means of an amine A-NH₂. Alternatively, starting from2,4-dichloropyrimidines A-1, it is possible to carry out the exchange inposition 2 of the pyrimidine with amines A-NH₂ and subsequentsubstitution of the chlorine in position 4 of the pyrimidine with aphenol OR², a thiophenol SR² or by coupling benzylmetal halidesHalMetR². As an alternative to the conventional nucleophilicsubstitutions, the transition metal-catalysed reaction of A-NH₂ with thecorresponding 2-chloropyrimidines A-2 is possible. R¹ and R² are eachsuitable groups for arriving at example compounds.

The nucleophilic aromatic substitutions at A-1, A-2 and A-3 are carriedout using methods known from the literature (e.g.: WO2008/040951) incommon solvents, such as for example THF, DCM, NMP, DMSO, toluene or DMFusing a base such as for example DIPEA, pyridine, LiOH, Cs₂CO₃ or KOtBu,an acid such as for example HCl or a Lewis acid such as for exampleZnCl₂. The alcohols OR², the sulphides SR², the organometallic compoundsHalMetR² and the amines A-NH₂ used are commercially obtainable or aresynthesised by methods known from the literature. The2-amino-4-oxopyrimidines, 2-amino-4-thiopyrimidines or2-amino-4-carbapyrimidines of type (1) which may be obtained directly bythese reaction methods may be further modified in R¹ and R² at asuitable point in the manner known from the literature or analogously tothe literature to form further derivatives of type (1). Thus, forexample, the groups R¹ and R² of directly accessible2-amino-4-oxo-pyrimidines, 2-amino-4-thiopyrimidines or2-amino-4-carbapyrimidines of type (1), which consist of a carboxylicacid, sulphonic acid, halogen- or amino-substituted aryl or heteroaryl,may be converted by reactions of substitution (at the heteroarylitself), alkylation, acylation, amination or addition.

Starting Materials

Where their preparation is not described, the starting materials arecommercially obtainable, known from the literature or easily obtainableby the skilled man using general methods, for example

-   4-amino-2-chloro-5-methoxy-benzoic acid,    4-amino-2-fluoro-5-methoxy-benzoic acid, (WO2008/040951)-   4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid (WO    2007003596)-   4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzoic    acid,-   4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-chloro-5-methoxy-benzoic    acid,-   4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-benzoic    acid, (analogously to WO 2007003596)-   7-amino-2-methyl-2,3-dihydro-isoindol-1-one (WO2005/016894)-   tert-butyl 4-benzylamino-3-fluoro-piperidine-1-carboxylate, (J. Med.    Chem. (1999), 42(12), 2087-2104).-   8-amino-2-methyl-3,4-dihydro-isoquinolin-1-one (WO2005/016894)-   benzyl    (3S,4S)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate    and-   benzyl    (3R,4R)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate    (WO 2004/058144)

7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one

7-amino-2-methyl-2,3-dihydro-isoindol-1-one (5 g) is suspended in amixture of ice (12.6 g) and conc. H₂SO₄ (8.62 g). Aqueous sodium nitritesolution (2.5 molar, 16 mL) is added dropwise, so that the temperaturedoes not rise above 0° C. and the solution is stirred for 15 min at thistemperature. Then H₂O (60 mL) is added and the solution is heated to 80°C. for 30 min. For working up it is combined with 10% NaCl solution (100mL) and extracted twice with 100 mL of CH₂Cl₂. The combined organicphases are dried on magnesium sulphate, filtered off from the desiccantand the solvent is eliminated in vacuo. The final purification iscarried out by preparative HPLC.

(R)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one and(S)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one a)2-methyl-3-methylene-7-nitro-2,3-dihydro-isoindol-1-one

Ethyl-2-acetyl-6-nitrobenzoate (11.12 g) is suspended in a mixture ofMeOH (70 mL) and MgSO₄. Methylamine (2 molar in THF, 28.13 mL) is addeddropwise and the solution is stirred for 15 min at this temperature.Then it is preheated to 70° C. for 18 h. The solvent is eliminated invacuo, the residue is taken up in dichloromethane (100 mL), washed withsodium chloride solution (10%) dried on magnesium sulphate, filtered offfrom the desiccant and the solvent is eliminated in vacuo. Forpurification it is recrystallised from toluene (250 mL).

b) 7-amino-2,3-dimethyl-2,3-dihydro-isoindol-1-one

2-methyl-3-methylene-7-nitro-2,3-dihydro-isoindol-1-one (13.96 g) issuspended in THF and mixed with a spatula tip of Pd/C (5%) andhydrogenated under H₂ pressure (3 bar). For working up the catalyst isfiltered off and the solvent is eliminated in vacuo.

c) 7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one

7-amino-2,3-dimethyl-2,3-dihydro-isoindol-1-one (11.45 g) is suspendedin a mixture of ice (27 g) and H₂SO₄ conc. (9.70 mL) and cooled to −10°C. Aqueous sodium nitrite solution (2.5 molar, 31.18 mL) is addeddropwise, so that the temperature does not rise above 0° C. and thesolution is stirred for 15 min at this temperature. Then H₂0 (135 mL) isadded and the solution is heated to 80° C. for 15 min. For working up itis combined with 10% NaCl solution (100 mL) and extracted twice with 100mL of CH₂Cl₂. The organic phase is extracted with NaOH solution (0.2molar) and then the aqueous phase is acidified (HCl aq. conc.) andre-extracted with CH₂Cl₂. The organic phase is dried on magnesiumsulphate, filtered off from the desiccant and the solvent is eliminatedin vacuo.

d) (R)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one and(S)-7-hydroxy-2,3-dimethyl-2,3-dihydro-isoindol-1-one

The two enantiomers are separated by chromatography of the racematethrough a chirally modified column (CHIRALCEL® OD-I, n-heptane/CH2Cl250/50).

7-hydroxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one a)2-(3-methoxy-phenyl)-2-methyl-propionitrile

NaH (14.13 g, 60%) is suspended in THF (400 mL) and cooled to 0° C.(3-methoxyphenyl)-acetonitrile (20 g) is dissolved in THF (20 mL) andadded dropwise. After 30 min at this temperature methyl iodide (19.46mL) in THF (20 mL) is added. After 16 h at 0° C. the reaction mixture iscombined with H₂O and extracted 3 times with CH₂Cl₂. The combinedorganic phases are dried on magnesium sulphate, filtered off from thedesiccant and the solvent is eliminated in vacuo. The residue is used inthe next reaction step without any further purification.

b) 2-(3-methoxy-phenyl)-2-methyl-propionic acid

2-(3-methoxy-phenyl)-2-methyl-propionitrile (28.55 g, 80%) is dissolvedin ethyleneglycol, combined with KOH (14.48 g) and heated to 150° C.After 18 h the reaction mixture is taken up in aqueous NaCl solution(10%) and extracted 3 times with CH₂Cl₂ and EtOAc. The aqueous phase isthen acidified with HCl (1 molar, aqueous) and extracted with EtOAc. Theresulting organic phase is extracted another 3 times with HCl (1 molar,aqueous), dried on magnesium sulphate, filtered off from the desiccantand the solvent is eliminated in vacuo. The residue is used in the nextreaction step without any further purification.

c) 1-(1-isocyanato-1-methylethyl)-3-methoxybenzene

2-(3-methoxy-phenyl)-2-methyl-propionic acid (24.40 g) is dissolved intoluene (120 mL) and cooled to 0° C. Triethylamine (16.61 mL) anddiphenylphosphorylazide (24.37 g) are added. After 0.5 h the mixture isheated to 110° C. After 3 h the reaction mixture is diluted with EtOAc,cooled to 0° C., extracted with NaHCO₃ solution and NaCl solution (H₂O,10%), dried on magnesium sulphate, filtered off from the desiccant andthe solvent is eliminated in vacuo. The residue is used in the nextreaction step without any further purification.

d) 7-methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one and7-methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one

FeCl₃ (40.00 g) is suspended in dichloroethane (10 mL) and cooled to 0°C. 1-(1-isocyanato-1-methylethyl)-3-methoxybenzene (21.40 g, dissolvedin 10 mL dichloroethane) is added dropwise. After 1.5 h H₂O is added andthe mixture is stirred for 15 min. After the addition of CH₂Cl₂ theaqueous phase is separated off and discarded. The organic phase isextracted with aqueous tartaric acid solution, dried on magnesiumsulphate, filtered off from the desiccant and the solvent is eliminatedin vacuo. The two regioisomers are separated using a silica gel column(cHex/EtOAc 20:80 to 0:100).

e) 7-methoxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one

7-methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.16 g) is dissolvedin THF (50 mL) and NaH (7.88 g) is added batchwise. After 5 min methyliodide (7.18 mL) is added. After 18 h at 0° C. the reaction mixture iscombined with H₂0/AcCN as well as Isolute and purified by RP HPLC.

f) 7-hydroxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one

7-methoxy-2,3,3-trimethyl-2,3-dihydro-isoindol-1-one (0.18 g) isdissolved in CH₂Cl₂ (4.5 mL) and cooled to −78° C. After the addition ofBBr₃ (1 molar in CH₂Cl₂, 2.92 mL) the reaction mixture is allowed towarm up to −10° C. within 3 h. For working up it is diluted with CH₂Cl₂and extracted with NaCl solution (H₂O, 10%). The organic phase is driedon magnesium sulphate, filtered off from the desiccant and the solventis eliminated in vacuo. The residue is used in the next reaction stepwithout any further purification.

(3R,4R)-3-methoxy-1-methyl-piperidin-4-ylamine a) benzyl(3R,4R)-4-tert-butoxycarbonylamino-3-methoxy-piperidine-1-carboxylate

benzyl(3S,4S)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate(5.00 g) is dissolved in THF (6 mL) and combined with 30 mL aqueous,semiconcentrated NaOH solution, benzyltriethylammonium chloride as wellas dimethylsulphate (2.26 mL). After 22 h H₂O (200 mL) is added and themixture is extracted with EtOAc (150 mL). The organic phase is dried onmagnesium sulphate, filtered off from the desiccant and the solvent iseliminated in vacuo. Purification is carried out using a silica gelcolumn (cHex/EtOAc 65/35).

b) tert-butyl ((3R,4R)-3-methoxy-piperidin-4-yl)-carbamate

Benzyl(3R,4R)-4-tert-butoxycarbonylamino-3-methoxy-piperidine-1-carboxylate(2.88 g) is dissolved in ethanol and combined with a spatula tip of Pd/Cand hydrogenated under H₂ pressure (4 bar). After 18 h the catalyst isfiltered off and the solvent is eliminated in vacuo. The residue is usedin the next reaction step without any further purification.

c) tert-butyl ((3R,4R)-3-methoxy-1-methyl-piperidin-4-yl)-carbamate

Tert-butyl ((3R,4R)-3-methoxy-piperidin-4-yl)-carbamate (2.88 g) isdissolved with formaldehyde (1.79 mL, 37% solution in H₂O) and aceticacid (100 μL) in DMF. Then Na(OAc)₃BH (12.59 g) is added. After 20 h thereaction mixture is combined with aqueous NaHCO₃ solution (saturatedwith NaCl) and extracted 5 times with EtOAc. The combined organic phaseis dried on magnesium sulphate, filtered off from the desiccant and thesolvent is eliminated in vacuo. The residue is used in the next reactionstep without any further purification.

d) (3R,4R)-3-methoxy-1-methyl-piperidin-4-ylamine

Tert-butyl ((3R,4R)-3-methoxy-1-methyl-piperidin-4-yl)-carbamate (3.01g) is combined with HCl (4 molar in dioxane, 25 mL). After 1 h thereaction mixture is freed from the solvent in vacuo and used in the nextstep without any further purification.

tert-butyl (3R,4S)-4-amino-3-fluoro-piperidine-1-carboxylate

Tert-butyl (3R,4S)-4-benzylamino-3-fluoro-piperidine-1-carboxylate (2.13g) is suspended in THF and mixed with a spatula tip of Pd(OH)₂ andhydrogenated under H₂ pressure (7 bar). For working up the catalyst isfiltered off and the solvent is eliminated in vacuo and the residue isused in the next step without any further purification.

Example 1: Benzyl2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoatea)7-(2,5-dichloro-pyrimidin-4-yloxy)-2-methyl-2,3-dihydro-isoindol-1-one

2,4,5-trichloropyrimidine (0.20 g) and7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one are dissolved in DCM (10mL), cooled to 0° C. and combined with caesium carbonate (0.75 g). Thecooling bath is removed and the mixture is stirred for 16 h. For workingup the mixture is combined with 10% NaCl solution (100 mL) and extractedthree times with 75 mL ethyl acetate. The combined organic phases aredried on magnesium sulphate, filtered off from the desiccant and thesolvent is eliminated in vacuo.

b) benzyl2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoate

7-(2,5-dichloro-pyrimidin-4-yloxy)-2-methyl-2,3-dihydro-isoindol-1-one(0.10 g), benzyl 4-amino-2-chloro-5-methoxy-benzoate (0.28 g), Pd₂dba₃(18 mg), X-Phos (37 mg) and Cs₂CO₃ are weighed into a microwave vial andargon flushing is carried out. Then toluene (1 mL) and NMP (50 μL) areadded, argon flushing is carried out again and the mixture is stirredfor 5 min at 150° C. in the microwave. For working up the mixture isdiluted with ACN (20 mL) and combined with Isolute (Separtis GmbH). Thesolvent is eliminated in vacuo and then purified by preparative HPLC.(IC₅₀=53 nmol)

Example 2:2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamidea)2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoicacid

Benzyl2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoate(75 mg) is dissolved in THF (150 mL), Pd(OH)₂ (0.01 g) is added and themixture is stirred for 2 h under H₂ gas. For working up the mixture isdiluted with ACN (20 mL) and Isolute is added. The solvent is filteredoff from the catalyst and the solvent is eliminated in vacuo.

b)2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoicacid (65 mg), TBTU (60 mg) and DIPEA (0.1 mL) are suspended in DMF (0.50mL) and stirred for 5 min 1-methylpiperidin-4-amine (18 mg) is added andthe reaction mixture is stirred for a further 20 min. The reactionmixture is purified by HPLC without working up. (IC₅₀=1 nmol).

The following compounds 3 to 215 are synthesised analogously, with thecorresponding 2-chloropyrimidines as educts:

TABLE 1 Examples 3-215 t_(Ret) (HPLC) MS PTK2 IC₅₀ No. Structure [min](M + H)⁺ [nM]  3

 1.90 558    3  4

 1.96 576    4  5

 1.94 574    2  6

 1.94 574    3  7

 1.97 574    5  8

 1.96 574    3  9

 2.03 592    4  10

 2.03 592    5  11

 2.04 592    7  12

 2.04 592    9  13

 2.12 604    10  14

 2.20 622    16  15

 1.99 590    3  16

 2.08 576    4  17

 2.02 576    5  18

 2.04 604    5  19

 2.07 590    6  20

 2.05 590    15  21

 1.79 556    2  22

 2.02 626    5  23

 2.19 515    10  24

 1.96 543    7  25

 2.04 574    4  26

 1.90 555    5  27

 1.75 459    9  28

 1.73 441    11  29

 2.00 483    12  30

 1.88 617    3  31

 1.85 545    3  32

 1.67 443    4  33

 1.63 461    10  34

 1.96 617    2  35

 1.95 617    2  36

 2.02 635    4  37

 2.06 635    4  38

 1.89 571    1  39

 1.83 587    2  40

 2.09 570    2  41

 2.17 588    3  42

 1.91 615   309  43

 2.06 620    12  44

 1.94 626    4  45

 1.83 471    9  46

 1.65 487    11  47

 1.79 603    1  48

 2.05 586    5  49

 2.11 604    7  50

 1.18 460    5  51

 1.73 454    11  52

 1.90 485    51  53

 1.90 554    9  54

 1.98 568    10  55

 2.08 582    8  56

 1.93 624    17  57

 1.96 554    9  58

 1.79 585    5  59

 1.10 430    26  60

 1.90 619    2  61

 1.86 623    2  62

 1.81 623    2  63

 1.81 623    4  64

 1.75 589    1  65

 1.84 607    1  66

 1.84 607    2  67

 1.67 385    2  68

 1.84 605    1  69

 1.87 589    1  70

 1.76 589    1  71

 0.26 488    75  72

 1.73 506    26  73

 1.99 396    60  74

 1.81 366   196  75

 1.79 378   400  76

 1.82 585    2  77

 1.84 566    2  78

 1.73 537    1  79

 1.71 348   400  80

 1.88 366   400  81

 1.77 571    1  82

 1.97 530    3  83

 1.89 480    2  84

 2.28 565    53  85

 2.15 420    29  86

 2.06 390    34  87

 1.75 390   227  88

 1.73 569    1  89

 1.89 509    1  90

 1.84 587    2  91

 1.65 545    3  92

 1.82 571    1  93

 2.05 443    1  94

 2.12 514    1  95

 1.73 446   400  96

 1.80 464    29  97

 2.01 517    4  98

 1.85 487    14  99

 1.87 501    36 100

 1.94 531    11 101

 1.87 529    1 102

 1.88 531    2 103

 1.00 407   400 104

 1.87 585    1 105

 1.76 589    1 106

 1.75 373    35 107

 2.23 575   400 108

 1.78 555    2 109

 1.51 503    16 110

 1.97 384    72 111

 1.84 589    1 112

 1.75 471    1 113

 1.85 531    2 114

 1.80 547    1 115

 1.97 605    1 116

 1.97 605    1 117

 1.87 587    1 118

 2.03 617    1 119

 1.86 619    1 120

 1.83 617    1 121

 1.86 629    1 122

 2.19 605    2 123

 1.80 562    3 124

 1.90 576    6 125

 1.84 563    1 126

 1.78 590    2 127

 2.00 615    2 128

 1.61 566    1 129

 1.99 540    2 130

 1.88 571    1 131

 1.73 589    1 132

 1.74 601    1 133

 1.73 641    1 134

 2.04 569    2 135

 1.98 548    28 136

 1.86 585    1 137

 1.86 585    1 138

 1.86 585    1 139

 1.79 559    1 140

 1.80 516    3 141

 1.72 502    1 142

 1.77 585    1 143

 1.68 551    1 144

 1.79 558    3 145

 1.78 585    1 146

 1.79 585    1 147

 1.81 569    1 148

 1.81 569    1 149

 1.71 621    1 150

 1.89 674    2 151

 1.82 508    2 152

 1.82 615    1 153

 1.90 576    5 154

 2.02 712    3 155

 1.85 659    2 156

 1.79 603    1 157

 1.75 589    1 158

 1.78 601    1 159

 1.82 615    1 160

 1.79 603    1 161

 1.84 599    1 162

 1.82 587    1 163

 1.84 599    1 164

 1.91 601    1 165

 2.07 615    2 166

 1.81 587    1 167

 1.74 573    2 168

 1.77 585    1 169

 1.70 581    1 170

 1.67 569    1 171

 1.81 592    4 172

 1.77 609    1 173

 1.74 597    1 174

 1.76 601    9 175

 1.87 619    10 176

 1.74 601   102 177

 1.82 619    92 178

 2.08 615   400 179

 2.16 633   400 180

 1.64 601    1 181

 1.40 504    1 182

 1.67 583    3 183

 1.68 516    2 184

 1.62 585    1 185

 1.94 576    6 186

 1.75 599    1 187

 1.64 472    2 188

 1.03 475    2 189

 2.04 556    11 190

 1.96 592    8 191

 1.77 615    1 192

 1.80 555    1 193

 1.72 555    1 194

585    1.82  3 195

 1.70 532    1 196

 1.75 546    3 197

 1.81 454    2 198

 1.54 491    1 199

 1.55 491    1 200

 2.02 357    1 201

 1.77 600    1 202

 1.82 616    2 203

 1.76 571    2 204

 1.95 619    2 205

 1.91 526    4 206

 1.88 603    2 207

 1.70 601    1 208

 1.75 609    1 209

 1.76 619    1 210

 1.68 601    1 211

 1.98 512    1 212

 1.72 615    1 213

 1.74 615    1 214

 1.82 528    4 215

 1.86 542    3

The following Examples describe the biological activity of the compoundsaccording to the invention without restricting the invention to theseExamples.

PTK2 Enzyme Test

This test uses active PTK2 enzyme (Invitrogen Code PV3832) andpoly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. The kinaseactivity is detected by means of the phosphorylation of the substrate ina DELFIA™ assay. The phosphorylated substrate is detected with theeuropium-labelled phosphotyrosine antibody PY20 (Perkin Elmer, No.:AD0038).

In order to determine concentration-activity curves with PTK2-inhibitorsthe compounds are serially diluted in 10% DMSO/H₂O and 10 μL of eachdilution are dispensed per well in a 96-well microtitre plate (clearU-shaped base plate, Greiner No. 650101) (the inhibitors are tested induplicates) and mixed with 10 μL/well of PTK2 kinase (0.01 μg/well).PTK2 kinase is diluted accordingly beforehand with kinase dilutionbuffer (20 mM TRIS/HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodiumorthovanadate, 10% glycerol with the addition of freshly prepared BSA(fraction V 1 mg/mL) and DTT (1 mM)). The test compound and the PTK2kinase are pre-incubated for 1 h at RT and shaken at 500 rpm. Then 20 μLATP Mix (30 mM TRIS/HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate,10 mM magnesium acetate, 0.1 mM EGTA, 1× Phosphatase Inhibitor Cocktail1 (Sigma, No.: P2850), 50 μM ATP (Sigma, No.: A3377; 15 mM stocksolution)) are added. The reaction is started by the addition of 10μL/well of poly (Glu,Tyr) substrate (25 μg/well poly (Glu, Tyr), 0.05μg/well biotinylated poly (Glu,Tyr) dissolved in 250 mM TRIS/HCl pH 7.5,9 mM DTT)—the final concentration of DMSO is 2%. After 1 h kinasereaction (the plates are shaken at 500 rpm), the reaction is stopped bythe addition of 12 μL/well of 100 mM EDTA, pH 8. And shaken for afurther 5 min at RT (500 U/min).

55 μL of the reaction mixture are transferred into a streptavidin plate(Strepta Well High Bind (transparent, 96-well) made by Roche, No.:11989685001) and incubated for 1 h at RT (shaking at 500 rpm). Then themicrotitre plate is washed three times with 200 μL/well D-PBS(Invitrogen, No.: 14190). 100 μL of 1:2000 diluted DELFIA Eu—N1Anti-Phosphotyrosine PY20 antibody (Perkin Elmer, No.: AD0038, 1:2000diluted in DELFIA test buffer (Perkin Elmer, No.: 1244-111)) is thenadded and it is incubated for 1 h at RT (shaking at 500 rpm). Then theplate is washed three times with 200 μL/well DELFIA washing buffer(Perkin Elmer, No.: 1244-114), 200 μL/well strengthening solution(Perkin Elmer, No.: 1244-105) is added and the whole is incubated for 10min at RT (shaking at 300 rpm).

The time-delayed europium fluorescence is then measured in a microtitreplate reader (Victor, Perkin Elmer). The positive control consists ofwells that contain solvent (2% DMSO in test buffer) and displayuninhibited kinase activity. Wells that contain test buffer instead ofenzyme act as a control for the background kinase activity.

The IC₅₀ values are determined from concentration-activity analyses byiterative calculation using a sigmoidal curve analysis algorithm (FIFTY,based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.

Soft-Agar Assay

This cellular test is used to determine the influence of PTK2-inhibitorson the growth of PC-3 prostate carcinoma cells in soft agar(‘anchorage-independent growth’). After an incubation time of two weeksthe cell vitality is demonstrated by Alamar Blue (resazurin) staining.

PC-3 cells (ATCC CRL-1435) are grown in cell culture flasks (175 cm²)with F12 Kaighn's Medium (Gibco, No.: 21127) which has been supplementedwith 10% foetal calf serum (Invitrogen, No.: 16000-044). The culturesare incubated in the incubator at 37° C. and 5% CO₂ and are run twice aweek. The test I carried out in microtitre plates (Greiner, No.: 655185) and consists of a lower layer made up of 90 μL of medium with 1.2%agarose (Invitrogen, 4% agarose gel 1× liquid 40 mL, No.: 18300-012),followed by a cell layer in 60 μL medium and 0.3% agarose and finally atop layer comprising 30 μL medium which contains the test compounds(without the addition of agarose). To prepare the lower layer, 4%agarose are decocted with 10× D-PBS (Gibco, No.: 14200) and H₂O and thusprediluted on 3% agarose in 1× D-PBS. The latter is adjusted withculture medium (F12 Kaighn's/10% FCS) and FCS to a final dilution of1.2% agarose in F12 Kaighn's Medium with 10% FCS. Each well of amicrotitre plate is supplied with 90 μL of the suspension for the lowerlayer and cooled to RT for 1 h. For the cell layer, PC-3 cells aredetached using trypsin (Gibco, 0.05%; No.: 25300), counted and seeded in60 μL F12 Kaighn's (10% FCS) with the addition of 0.3% agarose (37° C.).After cooling to RT for 1 h the test compounds (30 μL from serialdilutions) are added for quadruple measurements. The concentration ofthe test compounds usually covers a test range of between 10 μM and 0.3nM. The compounds (stock solution: 10 mM in 100% DMSO) are prediluted inF12 Kaighn's Medium+6% DMSO, to obtain a final concentration of 1% DMSO.The cells are incubated at 37° C. and 5% CO₂ in a steam-saturatedatmosphere for 14 days. The metabolic activity of living cells is thendemonstrated with the dye Alamar Blue (AbD Serotec, No.: BUF012B). To dothis, 18 μL/well of an Alamar Blue suspension are added and the whole isincubated for approx. 8 h in the incubator at 37° C. The positivecontrol consists of empty wells that are filled with a mixture of 18 μLof Alamar Blue reduced by autoclaving and 180 μL of F12 Kaighn's Medium(10% FCS). The fluorescence intensity is determined by means of afluorescence spectrometer (SpectraMAX GeminiXS, Molecular Devices). Theexcitation wavelength is 530 nm, the emission wavelength is 590 nm.

The EC₅₀ values are determined from concentrations-activity analyses byiterative calculation using a sigmoidal curve analysis algorithm (FIFTY,based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.

Phospho-PTK2 (pY397) Assay

This cellular test is used to determine the influence of PTK2-inhibitorson the state of the PTK2-phosphorylation at tyrosine 397 (pY397).

PC-3 cells (prostate carcinoma, ATCC CRL-1435) are grown in cell cultureflasks (175 cm²) with F12 Kaighn's Medium (Gibco, No.: 21127) with theaddition of 10% foetal calf serum (Invitrogen, No.: 16000-044). Thecultures are incubated in the incubator at 37° C. and 5% CO₂ and runtwice a week.

For the test, 2×10⁴ cells pro well/90 μL medium are plated out in96-well microtitre plates (Costar, No.: 3598) and incubated overnight inthe incubator at 37° C. and 5% CO₂. The test compounds (10 μL fromserial dilution) are added the next day. The concentration of the testcompounds usually covers a range of 50 μM and 0.8 nM. The test compounds(stock solution: 10 mM in 100% DMSO) are diluted in medium/medium 10%DMSO such that the final concentration is 1% DMSO. The cells are thenincubated in the incubator at 37° C. and 5% CO₂ for 2 h. Then theculture supernatant is removed and the cells are fixed with 150 μL 4%formaldehyde in D-PBS for 20 min at RT. The cell lawn is washed fivetimes with 200 μL 0.1% Triton X-100 in D-PBS for 5 min in each case andthen incubated for 90 min with blocking buffer (5% skimmed milk powder(Maresi Fixmilch) in TBST (25 mM Tris/HCl, pH 8.0, 150 mM NaCl, 0.05%Tween 20). The blocking buffer is replaced by 50 μL of the firstantibody anti-phospho PTK2 [pY397] rabbit monoclonal(Invitrogen/Biosource, No.: 44-625G), which is diluted 1:200 in blockingbuffer. For control purposes, alternatively a PTK2 [total] antibody(clone 4.47 mouse monoclonal, Upstate, No.: 05-537), diluted 1:400 inblocking buffer is used. This incubation is carried out at 4° C.overnight. Then the cell lawn is washed five times with 100 μL of 0.1%Tween in D-PBS for 5 min in each case and 50 μL/well of second antibodyare added. In order to detect bound phospho-PTK2 [pY397] antibody agoat-anti-rabbit antibody is used which is coupled with horseradishperoxidase (Dako, No.: P0448; 1:500 dilution in blocking buffer). Inorder to detect bound PTK2 [total]-antibodies a rabbit-anti-mouseantibody is used, which is also coupled with horseradish peroxidase(Dako, No.: PO161; 1:1000 dilution in blocking buffer). This incubationis carried out for 1 h at RT with gentle shaking. The cell lawn is thenagain washed five times with 100 μL of 0.1% Tween in D-PBS for 5 min ineach case. Peroxidase staining is carried out by adding 100 μL stainingsolution (1:1 mixture of TMB peroxidase substrate (KPL, No.: 50-76-02)and peroxidase solution B (H₂O₂) (KPL, No.: 50-65-02). The developmentof the stain takes place for 10-30 min in the dark. The reaction isstopped by the addition of 100 μL/well of a 1 M phosphoric acidsolution. The absorption is determined photometrically at 450 nm with anabsorption measuring device (VICTOR³ PerkinElmer). The inhibition of theanti-phospho PTK2 [pY397] immune staining is used to determine EC₅₀values. The staining with anti-PTK2 [total]-antibodies is for controlpurposes and should remain constant under the influence of inhibitor.The EC₅₀ values are determined from concentration-activity analyses byiterative calculation with the aid of a sigmoidal curve analysisalgorithm (FIFTY, based on GraphPAD Prism Version 3.03) with a variableHill coefficient.

The substances of the present invention are PTK2-kinase inhibitors. Inview of their biological properties the new compounds of general formula(1) or (1a), the isomers thereof and the physiologically acceptablesalts thereof are suitable for the treatment of diseases characterisedby excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g.psoriasis); diseases based on hyperplasia which are characterised by anincrease in the number of cells (e.g. fibroblasts, hepatocytes, bonesand bone marrow cells, cartilage or smooth muscle cells or epithelialcells (e.g. endometrial hyperplasia)); bone diseases and cardiovasculardiseases (e.g. restenosis and hypertrophy).

For example, the following cancers may be treated with compoundsaccording to the invention, without being restricted thereto:

brain tumours such as for example acoustic neurinoma, astrocytomas suchas fibrillary, protoplasmic, gemistocytary, anaplastic, pilocyticastrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma,subependymal large-cell giant cell astrocytoma and desmoplasticinfantile astrocytoma; brain lymphomas, brain metastases, hypophysealtumour such as prolactinoma, hypophyseal incidentaloma, HGH (humangrowth hormone) producing adenoma and corticotrophic adenoma,craniopharyngiomas, medulloblastoma, meningeoma and oligodendroglioma;nerve tumours such as for example tumours of the vegetative nervoussystem such as neuroblastoma, ganglioneuroma, paraganglioma(pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumourson the peripheral nervous system such as amputation neuroma,neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignantSchwannoma, as well as tumours of the central nervous system such asbrain and bone marrow tumours; intestinal cancer such as for examplecarcinoma of the rectum, colon, anus and duodenum; eyelid tumours(basalioma or adenocarcinoma of the eyelid apparatus); retinoblastoma;carcinoma of the pancreas; carcinoma of the bladder; lung tumours(bronchial carcinoma-small-cell lung cancer (SCLC), non-small-cell lungcancer (NSCLC) such as for example spindle-cell plate epithelialcarcinomas, adenocarcinomas (acinary, paillary, bronchiolo-alveolar) andlarge-cell bronchial carcinoma (giant cell carcinoma, clear-cellcarcinoma)); breast cancer such as ductal, lobular, mucinous or tubularcarcinoma, Paget's carcinoma; non-Hodgkin's lymphomas (B-lymphatic orT-lymphatic NHL) such as for example hair cell leukaemia, Burkitt'slymphoma or mucosis fungoides; Hodgkin's disease; uterine cancer (corpuscarcinoma or endometrial carcinoma); CUP syndrome (Cancer of UnknownPrimary); ovarian cancer (ovarian carcinoma-mucinous or serous cystoma,endometriodal tumours, clear cell tumour, Brenner's tumour); gallbladder cancer; bile duct cancer such as for example Klatskin tumour;testicular cancer (germinal or non-germinal germ cell tumours);laryngeal cancer such as for example supra-glottal, glottal andsubglottal tumours of the vocal cords; bone cancer such as for exampleosteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma,chondrosarcoma, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma,non-ossifying bone fibroma, osteofibroma, desmoplastic bone fibroma,bone fibrosarcoma, malignant fibrous histiocyoma, osteoclastoma or giantcell tumour, Ewing's sarcoma, and plasmocytoma, head and neck tumours(HNO tumours) such as for example tumours of the lips, and oral cavity(carcinoma of the lips, tongue, oral cavity), nasopharyngeal carcinoma(tumours of the nose, lymphoepithelioma), pharyngeal carcinoma,oropharyngeal carcinomas, carcinomas of the tonsils (tonsil malignoma)and (base of the) tongue, hypopharyngeal carcinoma, laryngeal carcinoma(cancer of the larynx), tumours of the paranasal sinuses and nasalcavity, tumours of the salivary glands and ears; liver cell carcinoma(hepatocellular carcinoma (HCC); leukaemias, such as for example acuteleukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acutemyeloid leukaemia (AML); chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer (papillary, tubular or mucinousadenocarcinoma, adenosquamous, squamous or undifferentiated carcinoma;malignant melanomas such as for example superficially spreading (SSM),nodular (NMM), lentigo-maligna (LMM), acral-lentiginous (ALM) oramelanotic melanoma (AMM); renal cancer such as for example kidney cellcarcinoma (hypernephroma or Grawitz's tumour); oesophageal cancer;penile cancer; prostate cancer; vaginal cancer or vaginal carcinoma;thyroid carcinomas such as for example papillary, follicular, medullaryor anaplastic thyroid carcinoma; thymus carcinoma (thymoma); cancer ofthe urethra (carcinoma of the urethra, urothelial carcinoma) and cancerof the vulva.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (1) may be used on their own or incombination with other active substances according to the invention,optionally also in combination with other pharmacologically activesubstances.

Chemotherapeutic agents which may be administered in combination withthe compounds according to the invention include, without beingrestricted thereto, hormones, hormone analogues and antihormones (e.g.tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproteroneacetate, finasteride, buserelin acetate, fludrocortisone,fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors(e.g. anastrozole, letrozole, liarozole, vorozole, exemestane,atamestane), LHRH agonists and antagonists (e.g. goserelin acetate,luprolide), inhibitors of growth factors (growth factors such as forexample “platelet derived growth factor” and “hepatocyte growth factor”,inhibitors are for example “growth factor” antibodies, “growth factorreceptor” antibodies and tyrosinekinase inhibitors, such as for examplegefitinib, lapatinib and trastuzumab); signal transduction inhibitors(e.g. imatinib and sorafenib); antimetabolites (e.g. antifolates such asmethotrexate, premetrexed and raltitrexed, pyrimidine analogues such as5-fluorouracil, capecitabin and gemcitabin, purine and adenosineanalogues such as mercaptopurine, thioguanine, cladribine andpentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g.anthracyclins such as doxorubicin, daunorubicin, epirubicin andidarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin,streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin,carboplatin); alkylation agents (e.g. estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas such as for example carmustin andlomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such asfor example vinblastine, vindesin, vinorelbin and vincristine; andtaxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g.epipodophyllotoxins such as for example etoposide and etopophos,teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and variouschemotherapeutic agents such as amifostin, anagrelid, clodronat,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotane, pamidronate and porfimer.

Suitable preparations include for example tablets, capsules,suppositories, solutions, —particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. In amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples that follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (1) 100 mglactose 140 mg corn starch 240 mg polyvinylpyrrolidone  15 mg magnesiumstearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (1) 80 mglactose 55 mg corn starch 190 mg  microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesiumstearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance according to formula (1) 50 mgsodium chloride 50 mg water for inj.  5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

The invention claimed is:
 1. A compound of the formula (1a),

wherein W and Y each independently of one another represent CH₂, O,N—R^(e) or N—OR^(e); A denotes a group, optionally substituted by one ormore identical or different R¹, selected from among C₃₋₁₀cycloalkyl, 3-8membered heterocycloalkyl, C₆₋₁₅aryl and 5-12 membered heteroaryl; R¹and R² each independently of one another denote hydrogen or a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(c) and/or R^(b); R³ denotes a group selectedfrom among hydrogen, halogen, —OR^(c), —OCF₃, —SR^(c), —NR^(c)R^(c),—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, C₁₋₃alkyl, C₁₋₃haloalkyl andC₁₋₃haloalkyloxy; each R^(a) is selected independently of one anotherfrom among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl; each R^(b) is a suitable group and isindependently selected from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃,═S, —SR^(c), ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c),═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c),—N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c),—OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c),—C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),—N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),—N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),—N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c); each R^(e) independently of oneanother denotes hydrogen or a group optionally substituted by one ormore identical or different R^(d) and/or R^(e) selected from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl; each R^(d) is a suitable group and isindependently selected from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃,═S, —SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e),═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))[C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e); each R^(e) independently of oneanother denotes hydrogen or a group optionally substituted by one ormore identical or different R^(f) and/or R^(g) selected from amongC₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl; each R^(f) is a suitable group and isindependently selected from among halogen and —CF₃; and each R^(g)independently of one another denotes hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl; or a pharmacologically acceptable acid addition saltthereof.
 2. A compound according to claim 1 wherein A is phenyl.
 3. Acompound according to claim 1 wherein R³ is Cl or CF₃.
 4. Apharmaceutical composition comprising a compound according to claim 1 ora physiologically acceptable salt thereof and an excipient or carrier.